中文摘要：

目的 探讨中国大样本队列肥厚型心肌病（HCM）患者的遗传学基础以及与不同基因型相关的表型严重性.方法 对北京大学人民医院心脏中心2002至2011年连续收录的179例无血缘关系的HCM患者（男119例,女60例）直接测序分析β肌球蛋白重链（MYH7）、肌球蛋白结合蛋白C（MYBPC3）和心脏肌钙蛋白T（TNNT2）基因突变情况,并进行临床评估.结果 共发现40例（22.3％）患者存在34种突变.79.4％ （27/34）的突变只出现1次,而仅MYH7的26位氨基酸可能为突变热点.突变基因分布情况为MYBPC3、MYH7和TNNT2分别占52.9％ （18/34）、35.3％ （12/34）和11.8％ （4/34）.2.2％ （4/179）的患者存在双突变.基因型阳性（40例）与阴性患者（139例）的发病年龄[（35.4±17.6）岁比（47.6±17.1）岁,P＜0.001]、左心室壁厚度[（21.2±5.7）mm比（19.0±5.3）mm,P=0.031]、晕厥发生率（27.5％比10.8％,P=0.019）、HCM家族史（35.0％比9.4％,P＜0.001）和心脏性猝死家族史（25.0％比2.2％,P＜0.001）差异均有统计学意义;在6.5年的随访期间具有更明显的心功能恶化（24.2％比5.0％,P=0.002）和猝死风险（9.1％比0,P=0.009）.MYBPC3与MYH7突变患者间临床参数和结局差异无统计学意义.本研究中的双突变患者具有恶性表型,而同一基因型（如MYH7-I736T、TNNT2-R92W）在不同患者中的表型严重程度不一.结论 MYBPC3是HCM患者中最多见的致病基因.尽管特定的基因或突变不能准确预测表型的严重性,但HCM患者如果存在肌小节基因突变,则提示更严重的结局.

英文摘要：

Objective To explore the genetic basis and phenotypic correlation with disease severity in a large cohort of Chinese patients with hypertrophic cardiomyopathy （HCM）.Methods A total of 179 unrelated Chinese HCM patients admitted to our department from 2002 to 2011 were enrolled in this study.Direct gene sequencing of β-myosin heavy chain （MYH7）,myosin binding protein-C （MYBPC3）,and cardiac troponin T （TNNT2） were performed and clinical data were obtained in these patients.Results A total of 34 mutations were identified in 40 patients （22.3%）,79.4% （27/34） mutations occurred only once and a possible hot spot,A26 in MYH7,was found.Distribution of mutations was 52.9% （18/34） （MYBPC3）,35.3 % （12/34） （MYH7） and 11.8% （4/34） （TNNT2） respectively.Double mutations were identified in 2.2% （4/179） patients.Genotype-positive patients were associated with an earlier symptom onset,severer left ventricular hypertrophy,a higher incidence of syncope,and were more likely to have positive family history of HCM or sudden cardiac death （SCD）,and were more likely to progress into heart failure（24.2% vs.5.0%,P =0.002） and at a higher risk of SCD（9.1% vs.0,P =0.009） during the 6.5-year follow-up.No statistical difference in any clinical parameters and outcomes was found between patients carrying MYBPC3 and MYH7 mutations.Double mutations were associated with malignant clinical progression in this cohort.Different phenotype severity could be seen in HCM patients with same genotype （e.g.MYH7-I736T,TNNT2-R92W）.Conclusion MYBPC3 is the most predominant gene mutation in this HCM cohort.The presence of a sarcomere mutation in patients with HCM is associated with poor clinical outcome,although no specific genes or mutations can exactly predict the severity of clinical phenotypes.